The present invention relates to the use of prostaglandins and prostaglandin analogues for the treatment of glaucoma and ocular hypertension. As used herein, the terms "prostaglandin" and "PG" shall refer to prostaglandins and derivatives and analogues thereof, except as otherwise indicated by context. Naturally-occurring prostaglandins, including prostaglandins of the F series (such as PGF.sub.2.alpha.), the E series (such as PGE.sub.2) and the D series (such as PGD.sub.2), are known to lower intraocular pressure (lOP) after topical ocular instillation, but can cause marked conjunctival hyperemia and/or inflammation with a number of associated side effects.
Hyperemia refers to vasodilation of conjunctival blood vessels, giving the eye a so-called "blood-shot" appearance. Prostaglandins may produce hyperemia directly through their pharmacological action on the vessels, which is undesirable due to its unattractive cosmetic appearance. Aside from its unattractive appearance, this type of hyperemia is usually without other signs and symptoms, and is of a benign nature. Prostaglandins may also produce hyperemia indirectly through production or exacerbation of inflammation in conjunctival tissues. In inflammation, other side effects such as conjunctival edema, cellular infiltration, itching, burning or foreign body sensation are typically present. Hyperemia associated with inflammation is of greater concern clinically, since edema and inflammatory cellular infiltration can produce pathologic changes of the conjunctival tissue and other mediators may become involved. There is therefore a clear distinction between the mechanisms of these two types of hyperemia: one being a benign type of vasodilation with no lasting consequences to patient; and the other being an irritative phenomenon which may result in tissue changes and discomfort.
The intolerable side effects associated with PGE's and PGF's stem from inflammation. Prostaglandins of the D series are also well-known for causing inflammation with associated hyperemia. This phenomenon has extended to D series analogues, such as BW245C. See, for example, Nakajima, M. et al. "Effects of prostaglandin D.sub.2 and its analogue, BW245C, on intraocular pressure in humans," Graefe's Arch. Clin. Exp. Ophthalmol., 229:411-413 (1991 ).
Woodward (U.S. Pat. No. 5,093,329) has attempted to overcome these side effects while maintaining the lOP-lowering effect; however, Woodward's data demonstrate only a brief lOP-lowering effect of these compounds in rabbits. In a subsequently published study, Crawford et al. (J. Glaucoma, 1:94-99 (1992)) found that SQ27986 (a compound of the type disclosed by Woodward) produces an initial lOP increase, but no significant lOP decrease, in normotensive monkeys.